A hybrid multiscale Monte Carlo algorithm (HyMSMC) to cope with disparity in time scales and species populations in intracellular networks

<p>Abstract</p> <p>Background</p> <p>The fundamental role that intrinsic stochasticity plays in cellular functions has been shown via numerous computational and experimental studies. In the face of such evidence, it is important that intracellular networks are simulated with stochastic algorithms that can capture molecular fluctuations. However, separation of time scales and disparity in species population, two common features of intracellular networks, make stochastic simulation of such networks computationally prohibitive. While recent work has addressed each of these challenges separately, a generic algorithm that can <it>simultaneously </it>tackle disparity in time scales <it>and </it>population scales in stochastic systems is currently lacking. In this paper, we propose the hybrid, multiscale Monte Carlo (HyMSMC) method that fills in this void.</p> <p>Results</p> <p>The proposed HyMSMC method blends stochastic singular perturbation concepts, to deal with potential stiffness, with a hybrid of exact and coarse-grained stochastic algorithms, to cope with separation in population sizes. In addition, we introduce the computational singular perturbation (CSP) method as a means of systematically partitioning fast and slow networks and computing relaxation times for convergence. We also propose a new criteria of convergence of fast networks to stochastic low-dimensional manifolds, which further accelerates the algorithm.</p> <p>Conclusion</p> <p>We use several prototype and biological examples, including a gene expression model displaying bistability, to demonstrate the efficiency, accuracy and applicability of the HyMSMC method. Bistable models serve as stringent tests for the success of multiscale MC methods and illustrate limitations of some literature methods.</p

Caesarean scar defect: a histopathological comparative study

Background: We have evaluated the validity of this syndrome in Indian patients and analysed the gynaecological indications for hysterectomy in women with history of caesarean sections. We have studied pathological changes in the scar area and compared the findings with matched cases without previous caesarean scar.Methods: A prospective observational case control study was done at tertiary care hospital (Seth GS Medical College and King Edward Memorial Hospital) over two years (December 2018 to December 2020) with universal sampling and enrolled all consenting eligible patients. After hysterectomy histopathological study of the specimens was done. Total cases: 16 hysterectomy samples with history of previous caesarean section. Total controls: 40 hysterectomy samples with history of no previous caesarean section. The difference between the two proportions was analysed using Chi square or Fisher exact test. All analysis was 2 tailed and the significance level was set at 0.05.Results: Women with history of previous caesarean scar had gynaecological symptoms related to the caesarean scar defect such as abnormal uterine bleeding, dysmenorrhea and chronic pelvic pain, post-menopausal bleeding and the most frequent clinical symptom related to the scar defect was abnormal uterine bleeding. The clinical symptoms were found to be associated with histopathological changes at scar site.Conclusions: This study compared caesarean cases and no caesarean controls and sheds light on the role of histopathology in detection of caesarean scar site changes. It helped in comparison of various factors affected due to the presence of caesarean scar and its long-term complications, leading to hysterectomy

The Bacillus anthracis protein MprF is required for synthesis of lysylphosphatidylglycerols and for resistance to cationic antimicrobial peptides

During inhalational anthrax, Bacillus anthracis survives and replicates in alveolar macrophages, followed by rapid invasion into the host's bloodstream, where it multiplies to cause heavy bacteremia. B. anthracis must therefore defend itself from host immune functions encountered during both the intracellular and the extracellular stages of anthrax infection. In both of these niches, cationic antimicrobial peptides are an essential component of the host's innate immune response that targets B. anthracis. However, the genetic determinants of B. anthracis contributing to resistance to these peptides are largely unknown. Here we generated Tn917 transposon mutants in the ΔANR strain (pXO1(−) pXO2(−)) of B. anthracis and screened them for altered protamine susceptibility. A protamine-sensitive mutant identified carried the transposon inserted in the BA1486 gene encoding a putative membrane protein homologous to MprF known in several gram-positive pathogens. A mutant strain with the BAS1375 gene (the orthologue of BA1486) deleted in the Sterne 34F2 strain (pXO1(+) pXO2(−)) of B. anthracis exhibited hypersusceptibility not only to protamine but also to α-helical cathelicidin LL-37 and β-sheet defensin human neutrophil peptide 1 compared to the wild-type Sterne strain. Analysis of membrane lipids using isotopic labeling demonstrated that the BAS1375 deletion mutant is unable to synthesize lysinylated phosphatidylglycerols, and this defect is rescued by genetic complementation. Further, we determined the structures of these lysylphosphatidylglycerols by using various mass spectrometric analyses. These results demonstrate that in B. anthracis a functional MprF is required for the biosynthesis of lysylphosphatidylglycerols, which is critical for resistance to cationic antimicrobial peptides

Translational Control of FOG-2 Expression in Cardiomyocytes by MicroRNA-130a

MicroRNAs are increasingly being recognized as regulators of embryonic development; however, relatively few microRNAs have been identified to regulate cardiac development. FOG-2 (also known as zfpm2) is a transcriptional co-factor that we have previously shown is critical for cardiac development. In this report, we demonstrate that FOG-2 expression is controlled at the translational level by microRNA-130a. We identified a conserved region in the FOG-2 3′ untranslated region predicted to be a target for miR-130a. To test the functional significance of this site, we generated an expression construct containing the luciferase coding region fused with the 3′ untranslated region of FOG-2 or a mutant version lacking this microRNA binding site. When these constructs were transfected into NIH 3T3 fibroblasts (which are known to express miR-130a), we observed a 3.3-fold increase in translational efficiency when the microRNA target site was disrupted. Moreover, knockdown of miR-130a in fibroblasts resulted in a 3.6-fold increase in translational efficiency. We also demonstrate that cardiomyocytes express miR-130a and can attenuate translation of mRNAs with a FOG-2 3′ untranslated region. Finally, we generated transgenic mice with cardiomyocyte over-expression of miR-130a. In the hearts of these mice, FOG-2 protein levels were reduced by as much as 80%. Histological analysis of transgenic embryos revealed ventricular wall hypoplasia and ventricular septal defects, similar to that seen in FOG-2 deficient hearts. These results demonstrate the importance of miR-130a for the regulation of FOG-2 protein expression and suggest that miR-130a may also play a role in the regulation of cardiac development

The mouse t complex distorter/sterility candidate, Dnahc8, expresses a γ-type axonemal dynein heavy chain isoform confined to the principal piece of the sperm tail

AbstractHeterozygosity for a t haplotype (t) in male mice results in distorted transmission (TRD) of the t-bearing chromosome 17 homolog to their offspring. However, homozygosity for t causes male sterility, thus limiting the spread of t through the population at large. The Ca2+-dependent sperm tail curvature phenotypes, “fishhook”, where abnormally high levels of sperm exhibit sharp bends in the midpiece, and “curlicue”, where motile sperm exhibit a chronic negative curving of the entire tail, have been tightly linked to t-associated male TRD and sterility traits, respectively. Genetic studies have indicated that homozygosity for the t allele of Dnahc8, an axonemal γ-type dynein heavy chain (γDHC) gene, is partially responsible for expression of “curlicue”; however, its involvement in “fishhook”/TRD, if any, is unknown. Here we report that the major isoform of DNAHC8 is copiously expressed, carries an extended N-terminus and full-length C-terminus, and is stable and equally abundant in both testis and sperm from +/+ and t/t animals. By in silico analysis we also demonstrate that at least three of the seventeen DNAHC8t mutations at highly conserved positions in wild-type DHCs may be capable of substantially altering normal DNAHC8 function. Interestingly, DNAHC8 is confined to the principal piece of the sperm tail. The combined results of this study suggest possible mechanisms of DNAHC8t dysfunction and involvement in “curlicue”, and support the hypothesis that “curlicue” is a multigenic phenomenon. They also demonstrate that the accelerated “fishhook” phenotype of sperm from +/t males is not directly linked to DNAHC8t dysfunction

Breakup of 42 MeV <SUP>7</SUP>Li projectiles in the fields of <SUP>12</SUP>C and <SUP>197</SUP>Au nuclei

Inclusive cross sections of a particles and tritons from the breakup of 42 MeV 7Li by 12C and 197Au targets are presented and analysed in the framework of the Serber model. Spectral distortions due to the targets and relevant reaction mechanisms are discussed